scholarly journals A novel GTPase, CRAG, mediates promyelocytic leukemia protein–associated nuclear body formation and degradation of expanded polyglutamine protein

2006 ◽  
Vol 172 (4) ◽  
pp. 497-504 ◽  
Author(s):  
Qingyu Qin ◽  
Ryoko Inatome ◽  
Azusa Hotta ◽  
Masaki Kojima ◽  
Hirohei Yamamura ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Dependent Manner ◽  
Polyglutamine Diseases ◽  
Promyelocytic Leukemia Protein ◽  
Localization Signal ◽  
Guanosine Triphosphatase ◽  
Interfering Rna ◽  
Polyglutamine Protein

Polyglutamine diseases are inherited neurodegenerative diseases caused by the expanded polyglutamine proteins (polyQs). We have identified a novel guanosine triphosphatase (GTPase) named CRAG that contains a nuclear localization signal (NLS) sequence and forms nuclear inclusions in response to stress. After ultraviolet irradiation, CRAG interacted with and induced an enlarged ring-like structure of promyelocytic leukemia protein (PML) body in a GTPase-dependent manner. Reactive oxygen species (ROS) generated by polyQ accumulation triggered the association of CRAG with polyQ and the nuclear translocation of the CRAG–polyQ complex. Furthermore, CRAG promoted the degradation of polyQ at PML/CRAG bodies through the ubiquitin–proteasome pathway. CRAG knockdown by small interfering RNA in neuronal cells consistently blocked the nuclear translocation of polyQ and enhanced polyQ-mediated cell death. We propose that CRAG is a modulator of PML function and dynamics in ROS signaling and is protectively involved in the pathogenesis of polyglutamine diseases.

scholarly journals C-terminal motifs in promyelocytic leukemia protein isoforms critically regulate PML nuclear body formation

2017 ◽  
Vol 130 (20) ◽  
pp. 3496-3506 ◽  
Author(s):  
Chuang Li ◽  
Qiongfang Peng ◽  
Xiao Wan ◽  
Haili Sun ◽  
Jun Tang
Keyword(s):  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Protein Isoforms ◽  
Promyelocytic Leukemia Protein ◽  
Body Formation

scholarly journals Ubiquitin-dependent Degradation of p73 Is Inhibited by PML

2004 ◽  
Vol 199 (11) ◽  
pp. 1545-1557 ◽  
Author(s):  
Francesca Bernassola ◽  
Paolo Salomoni ◽  
Andrew Oberst ◽  
Charles J. Di Como ◽  
Michele Pagano ◽  
...  
Keyword(s):  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Primary Cells ◽  
Tumor Suppressor P53 ◽  
Ubiquitin Proteasome Pathway ◽  
Mitogen Activated Protein ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

p73 has been identified recently as a structural and functional homologue of the tumor suppressor p53. Here, we report that p73 stability is directly regulated by the ubiquitin–proteasome pathway. Furthermore, we show that the promyelocytic leukemia (PML) protein modulates p73 half-life by inhibiting its degradation in a PML–nuclear body (NB)–dependent manner. p38 mitogen-activated protein kinase–mediated phosphorylation of p73 is required for p73 recruitment into the PML-NB and subsequent PML-dependent p73 stabilization. We find that p300-mediated acetylation of p73 protects it against ubiquitinylation and that PML regulates p73 stability by positively modulating its acetylation levels. As a result, PML potentiates p73 transcriptional and proapoptotic activities that are markedly impaired in Pml−/− primary cells. Our findings demonstrate that PML plays a crucial role in modulating p73 function, thus providing further insights on the molecular network for tumor suppression.

scholarly journals Arsenic-Induced SUMO-Dependent Recruitment of RNF4 into PML Nuclear Bodies

2010 ◽  
Vol 21 (23) ◽  
pp. 4227-4239 ◽  
Author(s):  
Marie-Claude Geoffroy ◽  
Ellis G. Jaffray ◽  
Katherine J. Walker ◽  
Ronald T. Hay
Keyword(s):  
Retinoic Acid Receptor ◽  
E3 Ligase ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Dependent Manner ◽  
Nuclear Trafficking ◽  
Sumo Modification ◽  
Ubiquitin E3 Ligase ◽  
Pml Nuclear Bodies

In acute promyelocytic leukemia (APL), the promyelocytic leukemia (PML) protein is fused to the retinoic acid receptor alpha (RAR). Arsenic is an effective treatment for this disease as it induces SUMO-dependent ubiquitin-mediated proteasomal degradation of the PML-RAR fusion protein. Here we analyze the nuclear trafficking dynamics of PML and its SUMO-dependent ubiquitin E3 ligase, RNF4 in response to arsenic. After administration of arsenic, PML immediately transits into nuclear bodies where it undergoes SUMO modification. This initial recruitment of PML into nuclear bodies is not dependent on RNF4, but RNF4 quickly follows PML into the nuclear bodies where it is responsible for ubiquitylation of SUMO-modified PML and its degradation by the proteasome. While arsenic restricts the mobility of PML, FRAP analysis indicates that RNF4 continues to rapidly shuttle into PML nuclear bodies in a SUMO-dependent manner. Under these conditions FRET studies indicate that RNF4 interacts with SUMO in PML bodies but not directly with PML. These studies indicate that arsenic induces the rapid reorganization of the cell nucleus by SUMO modification of nuclear body-associated PML and uptake of the ubiquitin E3 ligase RNF4 leading to the ubiquitin-mediated degradation of PML.

scholarly journals Promyelocytic Leukemia Protein (Pml) and Daxx Participate in a Novel Nuclear Pathway for Apoptosis

2000 ◽  
Vol 191 (4) ◽  
pp. 631-640 ◽  
Author(s):  
Sue Zhong ◽  
Paolo Salomoni ◽  
Simona Ronchetti ◽  
Ailan Guo ◽  
Davide Ruggero ◽  
...  
Keyword(s):  
Acid Treatment ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Retinoic Acid Treatment ◽  
Promyelocytic Leukemia Protein ◽  
Disease Remission ◽  
Activation Induced Cell Death ◽  
A Cell ◽  
Dependent Pathway

The promyelocytic leukemia protein (PML) gene of acute promyelocytic leukemia (APL) encodes a cell growth and tumor suppressor essential for multiple apoptotic signals. Daxx was identified as a molecule important for the cytoplasmic transduction of the Fas proapoptotic stimulus. Here, we show that upon mitogenic activation of mature splenic lymphocytes, Daxx is dramatically upregulated and accumulates in the PML nuclear body (NB) where PML and Daxx physically interact. In the absence of PML, Daxx acquires a dispersed nuclear pattern, and activation-induced cell death of splenocytes is profoundly impaired. PML inactivation results in the complete abrogation of the Daxx proapoptotic ability. In APL cells, Daxx is delocalized from the NB. Upon retinoic acid treatment, which induces disease remission in APL, Daxx relocalizes to the PML NBs. These results indicate that PML and Daxx cooperate in a novel NB-dependent pathway for apoptosis and shed new light in the role of PML in tumor suppression.

scholarly journals Identification of a putative nuclear localization signal in maspin protein shed light into its nuclear import regulation

2018 ◽  
Author(s):  
Jeffrey Reina ◽  
Lixin Zhou ◽  
Marcos R.M. Fontes ◽  
Nelly Panté ◽  
Nathalie Cella
Keyword(s):  
Subcellular Localization ◽  
Nuclear Localization ◽  
Hela Cells ◽  
Nuclear Import ◽  
Nuclear Localization Signal ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Biological Activities ◽  
Dependent Manner ◽  
Localization Signal

AbstractMaspin (SERPINB5) is a potential tumor suppressor gene with pleiotropic biological activities, including regulation of cell proliferation, death, adhesion, migration and gene expression. Several studies suggest that subcellular localization plays an essential role on maspin tumor suppression activity. In this study we investigated the molecular mechanisms underlying maspin nucleocytoplasmic shuttling. Anin vitronuclear-import assay using digitonin-permeabilized HeLa cells demonstrated that maspin enters the nucleus by an energy-and carrier-independent mechanism. However, previous studies indicated that maspin subcellular localization is regulated in the cell. Using a nuclear localization signal (NLS) prediction software, we identified a putative NLS in the maspin amino acid sequence. To distinguish between passive and regulated nuclear translocation, maspinNLS or the full-length protein (MaspinFL) were fused to 5GFP, rendering the construct too large to enter the nucleus passively. Unexpectedly, 5GFP-maspinNLS, but not maspinFL-5GFP, entered the nucleus of HeLa cells. Dominant-negative Ran-GTPase mutants RanQ69L or RanT24N, suppressed 5GFP-maspinNLS nuclear localization. In summary, we provide evidence that maspin translocates to the nucleus passively. In addition, we identified a peptide in the maspin protein sequence, which is able to drive a 5GFP construct to the nucleus in an energy-dependent manner.

scholarly journals Manipulation of Promyelocytic Leukemia Protein Nuclear Bodies by Marek’s Disease Virus Encoded US3 Protein Kinase

2021 ◽  
Vol 9 (4) ◽  
pp. 685
Author(s):  
Yifei Liao ◽  
Blanca Lupiani ◽  
Sanjay M. Reddy
Keyword(s):  
Protein Kinase ◽  
Disease Virus ◽  
Marek's Disease Virus ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Marek's Disease ◽  
Dependent Manner ◽  
Marek’S Disease Virus ◽  
Marek’S Disease ◽  
Promyelocytic Leukemia Protein

Promyelocytic leukemia protein nuclear bodies (PML-NBs) are dynamic nuclear structures, shown to be important for herpesvirus replication; however, their role in regulating Marek’s disease virus (MDV) infection has not been studied. MDV is an oncogenic alphaherpesvirus that causes lymphoproliferative disease in chickens. MDV encodes a US3 serine/threonine protein kinase that is important for MDV replication and gene expression. In this study, we studied the role of MDV US3 in regulating PML-NBs. Using an immunofluorescence assay, we found that MDV US3 disrupts PML and SP100 in a kinase dependent manner. In addition, treatment with MG-132 (a proteasome inhibitor) could partially restore the levels of PML and SP100, suggesting that a cellular proteasome dependent degradation pathway is involved in MDV US3 induced disruption of PML and SP100. These findings provide the first evidence for the interplay between MDV proteins and PML-NBs.

scholarly journals Contribution of the C-terminal Regions of Promyelocytic Leukemia Protein (PML) Isoforms II and V to PML Nuclear Body Formation

2012 ◽  
Vol 287 (36) ◽  
pp. 30729-30742 ◽  
Author(s):  
Yunyun Geng ◽  
Shamci Monajembashi ◽  
Anwen Shao ◽  
Di Cui ◽  
Weiyong He ◽  
...  
Keyword(s):  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Protein ◽  
Body Formation

scholarly journals Resistance to Virus Infection Conferred by the Interferon-Induced Promyelocytic Leukemia Protein

1998 ◽  
Vol 72 (2) ◽  
pp. 1043-1051 ◽  
Author(s):  
Mounira K. Chelbi-Alix ◽  
Frédérique Quignon ◽  
Luis Pelicano ◽  
Marcel H. M. Koken ◽  
Hugues de Thé
Keyword(s):  
Influenza A ◽  
Coiled Coil ◽  
Antiviral Effect ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Encephalomyocarditis Virus ◽  
Promyelocytic Leukemia Protein ◽  
Associated Proteins ◽  
Vesicular Stomatitis

ABSTRACT The interferon (IFN)-induced promyelocytic leukemia (PML) protein is specifically associated with nuclear bodies (NBs) whose functions are yet unknown. Two of the NB-associated proteins, PML and Sp100, are induced by IFN. Here we show that overexpression of PML and not Sp100 induces resistance to infections by vesicular stomatitis virus (VSV) (a rhabdovirus) and influenza A virus (an orthomyxovirus) but not by encephalomyocarditis virus (a picornavirus). Inhibition of viral multiplication was dependent on both the level of PML expression and the multiplicity of infection and reached 100-fold. PML was shown to interfere with VSV mRNA and protein synthesis. Compared to the IFN mediator MxA protein, PML had less powerful antiviral activity. While nuclear body localization of PML did not seem to be required for the antiviral effect, deletion of the PML coiled-coil domain completely abolished it. Taken together, these results suggest that PML can contribute to the antiviral state induced in IFN-treated cells.

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